| Abstract
| - Combinatorial and structure-based medicinal chemistry strategies were used together to advancea lead compound with an activity of Ki = 58 μM via a potency enhancement of >70 000-fold to ananalogue with an activity of Ki = 0.8 nM against influenza neuraminidase (A/Tokyo/67). Lead optimizationwas initiated using molecular modeling and combinatorial chemistry. Protein crystal structures revealedthat inconsistent structure−activity relationship (SAR) data resulted from different binding orientationsof the inhibitor core five-membered rings from one series to another. Binding modes for a series ofcompounds showed up to a 180° variation in orientation of the five-membered ring within the active site.Potent analogues were only achieved with chemical series that were observed to bind in the same orientationand yielded consistent SAR. In one series, consistent binding was obtained by an unprecedented occupationof a negatively charged binding pocket by a neutral methyl ester unit. The structural rationale for thisnovel SAR variation, based on protein crystallographic data, is given.
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